Miracles, Monsters, And Do-Re-Mi: A Variant Cultural History of The Word “Mutation”

None of us can cast stones for we are all fellow mutants together.

– Herman Muller (1950)

Until relatively recently, mutations were thought to be uncommon events that irregularly popped up around the genome, save for a few hotspots here and there. Unless exposed to a mutagen, DNA was conceptualized as a fairly stable molecule and the individual genome tolerated only a limited amount of variation. But large-scale DNA sequencing has demonstrated that gene mutations are pretty much the norm rather than the occasional exception. For example, a recent as yet unpublished study by Craig Ventner’s team of 10,545 deeply sequenced  human genomes found that each genome contributes on average 8,579 novel variants and uncovered more than 150 million variants in the coding and non-coding regions. If you run a complex genetic test and you don’t find a mutation of some sort, then there is probably something wrong with your sequencing technology. Of course, not all gene mutations are bad. Some are disease associated, some may confer biological advantage, some are neutral, and some are difficult to pin down. Differentiating among the good, the bad, and the neither-good-nor-bad has become a bête noire for anyone faced with interpreting the clinical significance of genetic test results for patients, especially when classifications differ among labs.

Although the word mutation carries some potently negative connotations, its definition implies objective scientific neutrality – “An alteration in the nucleotide sequence of DNA,” in its simplest form. But of necessity this is only a recent, post-Watson and Crick wording that itself has mutated over the centuries and that has often had some not-so-neutral musical, psychological, biological, pop culture, sociological, and religious ramifications. A hop, skip, and a jump through the history of the word reveals the richness and variety of its usage – as well as its darker sides.

According to the Oxford English Dictionary, one of the earliest recorded occurrences of the word goes back seven centuries to – who else? – Chaucer who used it in the sense of a change or alteration and whose Middle English rendered it as mutaycouns (“mutaycouns of fortune” from his translation of The Consolation of Philosophy by the Roman philosopher Boethius). Shakespeare used it similarly when, in King Lear, Edgar cries that the misfortunes of fate shorten our lives “World, World, O World! But that thy strange mutations make us hate thee, Life would not yield to age.”

Mutation was also used to describe the key Catholic belief in the transubstantiation of bread and wine into the body and blood of Jesus Christ during the sacrament of Communion. In the 1426 translation by John Lydgate of the French Cistercian monk Guilaume de Deguileville’s Pilgrimage of the Life of Man, a popular devotional book of the Middle Ages, we read about “That marvelous mutacion, Bred into flesshe, wyn into blood.”  This “marvelous mutacion” is a critical distinction between Protestant and Catholic theology, two religions that seemed to be at war with each other for most of the Middle Ages. Catholics believed that the Eucharist wafer dipped in wine transubstantiates into the actual body and blood of Christ whereas Protestants viewed it as a symbolic and ritual re-enactment of the Last Supper. Presaging future genetic connections between monsters and mutations, Martin Luther referred to transubstantiation as “a monstrous word for a monstrous idea.” During my Catholic school years, I remember joyously singing “Eat His Body, Drink His Blood, and we’ll sing a song of love. Allelu-Allelu-Alleluia!” Leonard Cohen does not have a thing over the Catholic hymnal.

Musically, mutation is the exchange of one syllable for another in an ascending note scale, as in solmization, i.e., associating a musical note with a human sound. Think do-re-mi-fa-so-la-ti-do. Mutation is also used in music to describe changes in singing voice that occur with age and gender, particularly the change that occur in boys’ voices as they transition to puberty, much to the chagrin of many choirmasters of Medieval Europe’s churches (a curiously coincidental link between religion and mutation). Choir boys were faced with a Sophie’s Choice of either genital mutilation or mutation.

Mutation also bridges musical and genetic definitions when DNA sequences are transformed into musical notes. For a couple of hundred bucks you can upload your 23andMe DNA sequence and have it translated into a piano solo, dance music, or a fully scored orchestral work. It’s a little bit funny, but the thing is what I really mean is that it gives new meaning to Elton John and Bernie Taupin’s 1970 hit single Your Song. As a leading candidate for the award of The World’s Worst Dancer, my daughters shudder to think what my DNA would sound like if it were translated into dance music and performed in public. No doubt it would contain many nonsense mutations although my daughters would hope it contains a very early premature stop codon. In a darkly comic coincidence that bridges modern music, Herman Muller’s above quote, and DNA, the musician Frank Zappa named his official fan club United Mutations, supposedly after reading his weird fan mail (think of how unusual the mail must have been if Zappa found it strange). And in another odd connection between mutation’s musical and biological connections, Zappa sounded like Darwin when he proclaimed “Without deviation from the norm, progress is not possible.”

The earliest reference I could find to the use of the word mutation in the context of evolution was in the 1869 publication Die Formenreihe des Ammonites subradiatus by Wilhelm Heinrich Waagen, a German paleontologist and geologist (no doubt somebody used the word before Waagen; there is always somebody else who was “really the first”). Based on his observations of fossil ammonites in the Punjabi Salt Range, Waagen proposed that evolution occurred slowly through minute mutations in a definite direction and that could be observed by careful examination of successive fossil strata, resulting in the eventual emergence of new species (though I think  he was thinking of mutations as anatomic rather than strictly genetic phenomena). Waagen was a devout Catholic who opposed Darwin’s evolutionary model and who tried to reconcile the fossil record with Genesis, suggesting that new species arose through new acts of divine creation

Mutation in its more modern sense arose with the re-discovery of Mendel’s work by de Vries, Correns, and Tschermak-Seysenegg and the flowering of modern genetics and evolutionary theory in 1900. de Vries in particular emphasized the importance of mutations to evolution in his magnum opus The Mutation Theory (1901-03). Gene mutations were now understood to be the engine that drove evolutionary change and chromosomes were thought to somehow carry genes. But the physical nature of mutations remained a mystery that was not resolved until the early 1950s when Alfred Hershey and Martha Chase identified DNA as the “hereditary material” and Watson and Crick famously resolved the structure and self-replicating mechanism of DNA.

Mutations could be adaptive or non-adaptive, though the presumption was that most mutations were evolutionary dead-ends and natural selection genetically purified the population (one can see the natural jump to eugenic ideologies). Creatures that were very different from their contemporaries presumably from underlying gene mutations were sometimes called, in the vocabulary of Richard Goldschmidt, “Hopeful Monsters,” evolutionary opportunities for saltatory speciation through chromosomal level mutations (Hopeful Monster and Hopeful Monsters are also the names of two different musical bands, as well as the title of 1990 novel by Nicholas Moseley). Others thought that hopeful monsters were only hopeful ideas and that speciation occurred through a more gradual dynamic balancing of winnowing and selection of small effect mutations.

Early 20th century eugenicists took the notion that mutations were largely negative and ran with it down some dark ethical alleyways. The “defective germ plasm” of immigrants from anywhere other than certain parts of northern and western Europe, people dwelling in the lower socio-economic rungs, the feeble-minded, and other undesirables made them genetic threats to the hereditarily healthy population. The solution to avoid becoming awash in defective germ plasm was to coercively or non-coercively discourage such genetic riff-raff from producing offspring. Eugenicists also encouraged genetically desirable people to have more offspring but such genetic hopefuls were not said to carry good mutations, just good genes.

The early 1930s saw the introduction of the far more neutral term allele, derived from allelomorph, which was itself introduced in 1902 by William Bateson, who also gave us the word “genetics.” Essentially alleles were versions of the same gene that differed on a DNA level. Although allele is in genetic publications, it has never really entered into the wider public vocabulary and discussion around genetic variation.

The geneticist Herman Muller had a career-long interest in genetic mutations, starting with his work with Drosophila in Thomas Hunt Morgan’s Fly Room at Columbia University and continuing with his Nobel-winning work on radiation induced mutations. His work, perhaps more than any other, was critical in the development of the idea that mutations were primarily harmful. In his influential 1950 American Journal of Human Genetics paper “Our Load of Mutations,” he viewed mutations as a “load” that the human species had to bear. However, he thought that most mutations were only slightly disadvantageous, and that each of us carries 8 slightly harmful mutations. Each mutation carried a selective disadvantage of 2.5%, and thus on average each person has a 20% chance of death or reproductive inefficiency as a result, under the assumption that humans were still living in the Neolithic. Muller worried that the comforts of the modern world allowed more maladaptive mutations to survive and increase, and that environmental exposure to ionizing radiation increased the frequency of  new mutations. This problem could be ameliorated by reducing the amount of man-made ionizing radiation and discouraging reproduction among those who carried the most mutations, “only” 3.5% of the population in his reckoning. Theodosius Dobzhansky served as a counter-point to Muller, arguing that variation was mostly adaptive and we should embrace the social and genetic diversity brought about by mutations (Muller’s paper and his disagreements with Dobzhansky are thoughtfully discussed in historian of biology Diane Paul’s 1987 paper “Our Load of Mutations” Revisited and is my primary source here).

Thus until about 60 years ago, with a few exceptions, mutations were largely viewed as having negative effects, while recognizing that some portion must be positive to allow adaptation and evolution to occur. Other than synonymous mutations in which the amino acid sequence is not altered, the notion that a mutation could have no phenotypic effect was not seriously discussed because mutations could only be inferred by their phenotypic effects. But in the 1960s, Motoo Kimura, among others, suggested that, based on studies of protein evolution, the rate of nucleotide substitutions was so high that it was difficult to believe they all had a positive or negative phenotypic effect. He felt that most mutations were neutral, that is, they have no measurable phenotypic effect and genetic variations among populations were largely the result of genetic drift, influenced by population size and dynamics. Mutations are like algae floating in the gene pool, pulled by the stochastic and unpredictable tides of populations

In Pop Culture, public fear of mutation arose in the context of the post World War II threat of nuclear war and the potential subsequent widespread exposure to ionizing radiation. Mutants in the public conception were typically monsters or super-humans with special powers that could be a blessing and/or a curse. Godzilla, The X-Men, the backwoods Southerners of  Deliverance, certain zombies (though apparently there are some finely nuanced arguments about the distinction between mutants and zombies), Spiderman, and the Hulk all owe their unique characteristics to mutations induced by radiation or inbreeding. For the most part, you don’t want to be these creatures. While it would be pretty cool to web-sling through the upper reaches of Manhattan’s skyscrapers, hulk-out to frighten off bad guys, or maybe even level a city or two, the message is almost always that being a mutant comes with the Faustian price of giving up the soul of your humanity. In conversation, to label someone a mutant is to suggest that they are very different, and usually in not such a good way. Even when used in a sort of positive context to describe super-athletes who seem to function on a different level than their competitors such as LeBron James, Diana Taurasi, Babe Didrikson Zaharias, Babe Ruth, Wayne Gretzky, Florence Joyner, Michael Phelps, or Diana Nyad, its use suggests that they are a different species from the rest of us, “freaks of nature” (ironically echoing the centuries old terminology “sports of nature” to describe biological specimens whose anatomy deviated significantly from the species type).

Not surprisingly, for many patients in genetics clinics, discovering that they carry a mutation, even in a recessive form, can be a narcissistic ego blow and affect desirability as a mate. If you carry a mutation you are implicitly a mutant. Connotations of the word mutation contribute to fears of having children with disabilities. Currently in medical genetics, and probably for the better, mutation is falling out of favor and there is a trend to replace it with a more neutral, or least less negative, terminology. Mutations are now described as variants that are categorized by qualifiers – benign polymorphism, uncertain significance, deleterious/pathogenic, etc. Although this nicely delineates the multiple effects and uncertainties of mutations, it doesn’t necessarily suggest that carrying a mutation is a good or normal state of affairs. And carrying a pathogenic variant, even a likely pathogenic variant, usually doesn’t make you feel too good about yourself when you wake up each morning and look at yourself in the mirror.

Mutations also cause much fretting and hand-wringing on the societal level. Witness the controversy around genetically modified organisms and worries that Frankenstein-like plants or animals will take over the environment like some real-life mutation, er, variant, of Day of The Triffids. Even CRISPR-Cas9 and other gene editing systems, which are intended to fix mutations, are criticized because of fears that they may unknowingly induce undesirable mutations in non-targeted parts of the genome.

At the end of the day, mutations are part of our biological identity. They are literally etched into our DNA, although we would be ignorant of the existence of most of them in the absence of DNA sequencing technology. None of us are Wild Types and all of us are Wild Types. We should embrace mutations, not reject them (well, at least most of them). Mutation is the norm for life, not the exception. Despite their typical neutrality, fear of mutations has been used to justify religious wars, castration of pre-pubescent boys, sterilization of the “unfit,” and to engender deep-rooted psychological fears in parents and in societies. Muller and Zappa were both right – we are all mutants and we should be united. But it turns out that being a mutant is usually not such a bad thing.

For an excellent short review of the concept of mutations in the history of biology, see Mutation: The History of An Idea From Darwin To Genomics by Elof Axel Carlson, Cold Spring Harbor Laboratory Press, 2011. Once again thanks to Emily Singh for help with graphics. 


Filed under Robert Resta

3 responses to “Miracles, Monsters, And Do-Re-Mi: A Variant Cultural History of The Word “Mutation”

  1. Variant variant variant (I’m practicing) variant variant variant

  2. Judith D. Widmann

    Quite a dazzling display of erudition. If it were not by Robert Resta, I would assume it was written by someone with way too much time on his hands. Bravo for an article of astonishing reach, depth and information.

  3. Shannon Ryan

    What a great read! It was a lecture by Charles Scriver, somewhat similar to this article, that brought me to the world of genetic counseling. Thank you.

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